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INTRODUCTION
Renal ischemia/reperfusion (rI/R) is an important cause
of death worldwide. The risk of mortality due to rI/R is
two to three times higher for those with acute lung
injury (ALI) [1–3], so it is crucial to determine ways of
inhibiting this complication. Treatments regulating
blood glucose concentrations, blood pressure and
oxidative stress have not been found to reduce deaths
associated with rI/R-induced ALI [4, 5].
Augmented serum concentrations of inflammatory
factors have been recognized as strong predictors of
rI/R risk and ALI development [6]. Increased
inflammatory protein levels activate the pyroptosis-
related nucleotide oligomerization domain (NOD)-like
receptor pyrin domain-containing 3 (NLRP3)
inflammasome, an important stimulator of rI/R-
induced ALI [2, 7]. NLRP3 induces interleukins 18
(IL-18) and 1β (IL-1β), inflammatory proteins that are
important contributors to numerous inflammatory
disorders [8–10]. On the other hand, NLRP3 suppresses
sirtuin 1 (SIRT1), a recognized inhibitor of alveolar
macrophage injury [11, 12]; thus, restoring SIRT1
levels could be a promising way to ameliorate NLRP3
inflammasome-induced alveolar macrophage activation.
There is clear evidence that inhibiting the NLRP3
inflammasome reduces inflammatory responses [13],
and NLRP3 inflammasome antagonists have mostly
been successful in treating rI/R [14–16], but their
effects on rI/R-induced ALI have not been reported.
The γ-aminobutyric acid receptor antagonist propofol,
an intravenous hypnotic drug that has been used
www.aging-us.com AGING 2021, Vol. 13, No. 1
Propofol reduces renal ischemia/reperfusion-induced acute lung
injury by stimulating sirtuin 1 and inhibiting pyroptosis
Zhaohui Liu1, Yanli Meng2, Yu Miao3, Lili Yu1, Qiannan Yu1
1Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou,
Hebei, China 2Department of Gastroenterology, Cangzhou Central
Hospital, Cangzhou, Hebei, China 3Department of Neurosurgery,
Cangzhou Central Hospital, Cangzhou, Hebei, China
Correspondence to: Zhaohui Liu; email:
[email protected], https://orcid.org/0000-0002-7467-9795
Keywords: propofol, renal ischemia/reperfusion, pyroptosis, SIRT1,
acute lung injury Received: July 9, 2020 Accepted: September 21,
2020 Published: December 1, 2020
Copyright: © 2020 Liu et al. This is an open access article
distributed under the terms of the Creative Commons Attribution
License (CC BY 3.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original author and
source are credited.
ABSTRACT
The activation of pyroptosis is an important feature of renal
ischemia/reperfusion (rI/R)-induced acute lung injury (ALI).
Propofol, a general anesthetic, is known to inhibit inflammation in
I/R-induced ALI. We investigated whether propofol could suppress
pyroptosis during rI/R-induced ALI by upregulating sirtuin 1
(SIRT1). We generated an in vivo model of rI/R-induced ALI by
applying microvascular clamps to the renal pedicles of rats for 45
min. Pathological studies revealed that rI/R provoked substantial
lung injury and inflammatory cell infiltration. The rI/R stimulus
markedly activated pyroptotic proteins such as NLRP3, ASC, caspase
1, interleukin-1β and interleukin-18 in the lungs, but reduced the
mRNA and protein levels of SIRT1. Propofol treatment greatly
inhibited rI/R-induced lung injury and pyroptosis, whereas it
elevated SIRT1 expression. Treatment with the selective SIRT1
inhibitor nicotinamide reversed the protective effects of propofol
during rI/R-induced ALI. Analogous defensive properties of propofol
were detected in vitro in rat alveolar macrophages incubated with
serum from the rI/R rat model. These findings indicate that
propofol attenuates rI/R-induced ALI by suppressing pyroptosis,
possibly by upregulating SIRT1 in the lungs.
Research Paper
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extensively to induce and maintain sedation and general
anesthesia, has been found to suppress inflammation in
I/R-induced ALI, and its adverse effects are
insignificant [17–19]. Propofol is known to prevent
alveolar macrophage activation, but the mechanism is
not well understood [20]. In this study, we assessed the
effects of propofol on NLRP3 inflammasome
activation, SIRT1 expression, inflammatory factor
release and oxidative stress in rI/R-induced ALI.
RESULTS
Propofol ameliorates the rI/R-induced release of
pyroptotic proteins and inflammatory cytokines in
NR8383 cells
In this study, we first examined the effects of propofol
on the rI/R-induced activation of pyroptotic proteins.
NR8383 rat alveolar macrophages were treated with
serum from a rat model of rI/R, with or without
propofol treatment. Then, Western blotting was
performed to measure the protein levels of cleaved
caspase 1 (P10), apoptosis-associated speck-like
protein containing a CARD (ASC) and NLRP3. As
indicated in Figure 1A, 1B, stimulation with serum
from rI/R rats increased P10 levels 4.2-fold, ASC
levels 3.6-fold, and NLRP3 levels 3.7-fold. However,
the administration of 50 and 100 μM propofol reduced
the levels of these three proteins dose-dependently in
rI/R serum-treated cells (P
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were used as controls. Compared with the sham
treatment, rI/R increased the lung injury score 10.5-
fold, the fluorescence intensity of myeloperoxidase
13.9-fold, the fluorescence intensity of F4/80 10.7-
fold, and the apoptotic index (%) 10.9-fold (Figure 4).
Treatment of rI/R rats with propofol (5 or 10 mg/kg)
remarkably and dose-dependently reduced these four
measures (P
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Figure 2. Propofol suppresses the rI/R-induced downregulation of
SIRT1 in rat alveolar macrophages. NR8383 cells were incubated with
serum from sham or rI/R rats, with or without propofol (50 or 100
μM) for 24 h. (A) Real-time PCR was used to measure SIRT1 mRNA
levels. (B) Western blotting was used to measure SIRT1 protein
levels (*P < 0.05 vs. sham; #P < 0.05 vs. rI/R).
Figure 3. The SIRT1 inhibitor nicotinamide prevents propofol
from reducing rI/R-induced pyroptosis in rat alveolar macrophages.
NR8383 cells were incubated with serum from sham or rI/R rats, with
or without propofol (100 μM) and/or nicotinamide (1 mM) for 24 h.
(A) Western blotting was used to measure the protein levels of
cleaved caspase 1 (P10), ASC and NLRP3. (B) ELISAs were used to
determine the protein levels of IL-18 and IL-1β (*P < 0.05 vs.
sham; #P < 0.05 vs. rI/R; $P < 0.05 vs. rI/R + propofol).
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and the fluorescence intensity of caspase 1 12.2-fold
compared with the sham operation. Propofol treatment
at 5 and 10 mg/kg dose-dependently reduced the
levels of these three proteins in the lungs of rI/R rats
(P
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We also explored whether the propofol-induced
inactivation of pyroptotic proteins inhibited IL-18 and
IL-1β secretion in the lungs of rats. An ELISA indicated
that IL-1β levels in the lungs were 54.8 pg/mL in the
sham group, but increased to 294.9 pg/mL after 24 h of
rI/R (Figure 5D, 5E). Treatment of rI/R rats with
propofol at 5 and 10 mg/kg reduced IL-1β levels to
187.4 and 106.4 pg/mL, respectively (P
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Propofol prevents the rI/R-induced downregulation
of SIRT1 in the lungs of rats
Subsequently, we assessed the effects of propofol on the
mRNA and protein levels of SIRT1 in the lungs of rI/R
rats. An immunofluorescence analysis indicated that
rI/R reduced the fluorescence intensity of SIRT1 to 21%
of the sham level, whereas further treatment with
propofol at 5 and 10 mg/kg increased it to nearly 55%
and 84% of the sham level, respectively (P
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Figure 7. The inhibition of SIRT1 prevents propofol from
ameliorating the morphological characteristics of ALI and
suppressing pyroptosis in the lungs of rI/R rats. Rats were
subjected to rI/R, with or without propofol (10 mg/kg) and/or
nicotinamide (60 mg/kg) treatment for 24 h. (A) H and E analysis
was performed, and the lung injury score was determined. (B)
Immunohistochemistry was used to measure the fluorescence intensity
of myeloperoxidase. (C) Immunofluorescence analysis was used to
measure the fluorescence intensity of F4/80. (D) TUNEL analysis was
used to measure the apoptotic index (%). (E–G) Immunofluorescence
analyses were used to measure the fluorescence intensity levels of
NLRP3, ASC and caspase 1. (H, I) ELISAs were used to measure the
protein levels of IL-1β and IL-18 (*P < 0.05 vs. sham; #P <
0.05 vs. rI/R; $P < 0.05 vs. rI/R + propofol).
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DISCUSSION
In this investigation, we first stimulated NR8383 rat
alveolar macrophages with serum from rI/R rats and
assessed the effects of propofol on numerous indicators of
rI/R injury, including the activation of the NLRP3
inflammasome, the induction of various other pyroptosis-
related inflammatory molecules and the suppression of
SIRT1. Our results revealed that, at clinically relevant
doses, propofol hindered each of these features of
pyroptosis. IL-1β and IL-18 are crucial activation
elements of the NLRP3 inflammasome during pyroptosis
[21], and their production is known to be activated by I/R
and sepsis but suppressed by propofol [22–24].
Accordingly, the present results indicated that propofol
could inhibit the activation of IL-1β and IL-18 in rat
alveolar macrophages and lung tissues during rI/R.
Inhibiting the activation of the pyroptosis-related
NLRP3 inflammasome is considered a key treatment
strategy for several chronic inflammatory disorders;
however, a harmless and dependable therapy remains to
be identified. Using lung tissues from a rat model of
rI/R-induced ALI, we confirmed our in vitro findings that
propofol could attenuate pyroptosis by inhibiting
the expression of pyroptotic proteins and enhancing the
expression of SIRT1 [25, 26]. These results extended
previous findings that propofol could stop the
progression of rI/R by reducing the levels of pyroptotic
proteins [27].
Notably, our study also revealed that SIRT1 was a crucial
conveyer of the beneficial effects of propofol, as
demonstrated by the results of inhibiting SIRT1 using
nicotinamide. Propofol has been reported to activate
SIRT1 in hepatic I/R tissues and human umbilical vein
endothelial cells [28, 29]. We found that propofol
enhanced SIRT1 expression in NR8383 cells, suggesting
that propofol could be used to inhibit pulmonary disorders
by inducing SIRT1. Further in vitro and in vivo research is
needed to determine the mechanisms whereby propofol
exerts these pro-SIRT1, anti-NLRP3 and anti-pyroptotic
effects during rI/R-induced ALI.
MATERIALS AND METHODS
Cell culture and treatment
NR8383 cells were obtained from the cell bank of the
Shanghai Institute of Cell Biology, Chinese Academy of
Sciences (Shanghai, China). The cells were grown in
Dulbecco’s modified Eagle’s medium with 10% fetal
bovine serum at 37° C in a humidified incubator (5%
CO2). The cells were treated with serum from rI/R rats,
with or without propofol (50 or 100 μM) and/or
nicotinamide (1 mM).
rI/R model establishment and drug treatment
Sprague-Dawley rats (220-250 g) were obtained from
the Experimental Animal Center of Hebei Medical
University (Hebei, China), and were housed in a rat
facility under representative experimental conditions for
seven days before the studies began. All the
experiments were conducted according to the National
Institutes of Health Guidelines for the Care and Use of
Experimental Animals, and the animal procedures were
approved by Cangzhou Central Hospital. The rats
received water and ordinary chow ad libitum.
An in vivo model of rI/R-induced ALI was generated by applying
microvascular clamps to the renal pedicles of
rats for 45 min. The effects of propofol on rI/R-induced
ALI were evaluated using the following five randomly
assigned groups of rats (n = 8/group): the sham group
(subjected to the same operation, without the clamping of
the renal pedicles), the propofol (10 mg/kg) group, the
rI/R group, the rI/R + propofol (5 mg/kg) group and the
rI/R + propofol (10 mg/kg) group. The effects of the
SIRT1 inhibitor nicotinamide were assessed using the
following five randomly assigned groups of rats (n =
8/group): the sham group, the nicotinamide (60 mg/kg)
group, the rI/R group, the rI/R + propofol (10 mg/kg)
group and the rI/R + propofol (10 mg/kg) + nicotinamide
(60 mg/kg) group. The treatment process was performed
as previously described by Liu et al [2, 3]. The rats were
sacrificed via intraperitoneal administration of 120 mg/kg
sodium thiopental, 24 h after rI/R with or without the
additional treatments. Lung samples were obtained for
pathological, molecular and biological studies.
H&E analysis
H&E staining was performed at 37° C to prepare the
lung samples for morphological examination. The
degree of lung injury was graded histologically using
the Murakami method by an investigator blinded to the
treatment groups. Twenty-four areas of the lung
parenchyma were scored separately for edema,
congestion, hemorrhage and inflammation on a scale
from 0 to 4 (0, absent and appears normal; 1, light; 2,
moderate; 3, strong; and 4, intense). Image-Pro Plus
software 4.5 (Media Cybernetics, Silver Spring, MD,
USA) was used for image analysis.
Immunohistochemistry
In brief, lung tissues from the aforementioned groups of
rats were fixed with paraformaldehyde (4%) at 37° C
for 10 min. Subsequently, 0.1% Triton X-100 in Tris-
buffered saline with Tween 20 (TBST) was used to
permeabilize the lung sections for 15 min. Then, TBST
containing 2.5% fetal bovine serum and 5% bovine
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serum albumin was used to block the lung sections, and
an anti-myeloperoxidase primary antibody (AF7494,
Beyotime, 1:50) was applied at 4° C overnight. The
lung sections were then washed three times and treated
with a secondary antibody (A0181, Beyotime, 1:100) at
37° C for 1 h.
TUNEL analysis
A TUNEL analysis was performed using a cell death
assay kit to assess lung apoptosis, as described
previously. TUNEL-positive nuclei exhibited green
fluorescence, while nuclei from TUNEL-negative cells
exhibited blue fluorescence. The degree of apoptosis
was calculated as the quantity of apoptotic cells/the
whole number of cells measured×100%.
Immunofluorescence analysis
Lung sections from the aforementioned groups of rats
were washed three times with phosphate-buffered saline
and then treated with primary antibodies against F4/80,
NLRP3, ASC, caspase 1 and SIRT1 at 4° C overnight.
Subsequently, the tissues were probed with a secondary
antibody (A0423, Beyotime, 1:500), washed with
phosphate-buffered saline and sealed with glycerin
(95%). A fluorescence microscope was used to visualize
the fluorescence indicators.
Real-time PCR analysis
An RNeasy Micro Kit was used to isolate total RNA
from NR8383 cells and rat lung tissues according to the
manufacturer’s directions (QIAGEN, UK). A Nanodrop
spectrophotometer was used to measure RNA
levels. Complementary DNA was obtained from 1 μg of
RNA using the iScriptTM
Reverse Transcription
Supermix. Then, rat SIRT1 mRNA transcripts were amplified with a
SYBR Green-based real-time PCR
assay (Invitrogen) on an ABI 7500 platform. GAPDH
was used to normalize the data according to the 2-ΔΔCt
method.
Western blotting assay
Radioimmunoprecipitation assay buffer with protease
and phosphatase inhibitors was used to lyse the NR8383
cells. Sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (10%) was used to separate the proteins
from 20 μg of cell lysate, and then the proteins were
transferred to polyvinylidene fluoride membranes.
Primary antibodies against NLRP3, ASC, P10, SIRT1
and β-actin (Beyotime, Wuhan, China) were used to
blot the membranes, and then the corresponding
secondary antibodies were applied (horseradish
peroxidase-labeled antibody; Beyotime). PierceTM
ECL
Plus Western blot substrate was used to visualize the
immunoblots.
ELISA analysis
The supernatants of NR8383 cells and homogenates of
rat lung tissues were evaluated for their concentrations
of IL-18 and IL-1β. ELISA kits were acquired from
Boster Biological Technology Co. Ltd. and used
according to the manufacturer’s directions. The results
were obtained using spectrometry on a 96-plate reader.
Statistical analysis
The findings are presented as the mean ± standard
derivation. Statistical analyses were carried out using
one-way analysis of variance followed by Bonferroni’s
post-test comparisons in GraphPad Prism 8. P values
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